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Real-time visualization and quantitation of vascular permeability in vivo: implications for drug delivery.
Pink DB, Schulte W, Parseghian MH, Zijlstra A, Lewis JD
(2012) PLoS One 7: e33760
MeSH Terms: Animals, Capillary Permeability, Cell Line, Chick Embryo, Chorioallantoic Membrane, Doxorubicin, Drug Delivery Systems, Evans Blue, Humans, Interleukin-2, Microscopy, Neoplasms, Neovascularization, Pathologic, Time-Lapse Imaging, Transplantation, Heterologous, Tumor Microenvironment, Vascular Endothelial Growth Factor A
Show Abstract · Added December 30, 2013
The leaky, heterogeneous vasculature of human tumors prevents the even distribution of systemic drugs within cancer tissues. However, techniques for studying vascular delivery systems in vivo often require complex mammalian models and time-consuming, surgical protocols. The developing chicken embryo is a well-established model for human cancer that is easily accessible for tumor imaging. To assess this model for the in vivo analysis of tumor permeability, human tumors were grown on the chorioallantoic membrane (CAM), a thin vascular membrane which overlays the growing chick embryo. The real-time movement of small fluorescent dextrans through the tumor vasculature and surrounding tissues were used to measure vascular leak within tumor xenografts. Dextran extravasation within tumor sites was selectively enhanced an interleukin-2 (IL-2) peptide fragment or vascular endothelial growth factor (VEGF). VEGF treatment increased vascular leak in the tumor core relative to surrounding normal tissue and increased doxorubicin uptake in human tumor xenografts. This new system easily visualizes vascular permeability changes in vivo and suggests that vascular permeability may be manipulated to improve chemotherapeutic targeting to tumors.
1 Communities
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17 MeSH Terms
Agonistic antibody to CD40 boosts the antitumor activity of adoptively transferred T cells in vivo.
Liu C, Lewis CM, Lou Y, Xu C, Peng W, Yang Y, Gelbard AH, Lizée G, Zhou D, Overwijk WW, Hwu P
(2012) J Immunother 35: 276-82
MeSH Terms: Adoptive Transfer, Animals, Antibodies, Monoclonal, Antigen Presentation, B7-1 Antigen, B7-2 Antigen, Bone Marrow Cells, CD40 Antigens, Cell Line, Female, Interleukin-2, Melanoma, Experimental, Mice, Mice, Inbred C57BL, Mice, Knockout, T-Lymphocytes, gp100 Melanoma Antigen
Show Abstract · Added April 11, 2014
CD40, a member of the tumor necrosis factor receptor superfamily, is broadly expressed on antigen-presenting cells and other cells, including fibroblasts and endothelial cells. Binding of CD40 and its natural ligand CD40L (CD154) triggers cytokine secretion, and increased expression of costimulatory molecules is required for T-cell activation and proliferation. However, to our knowledge, the use of agonistic antibodies to CD40 to boost adoptively transferred T cells in vivo has not been investigated. The purpose of this study was to determine whether anti-CD40 monoclonal antibody (mAb) in combination with interleukin (IL)-2 could improve the efficacy of in vitro-activated T cells to enhance antitumor activity. Mice bearing B16 melanoma tumors expressing the gp100 tumor antigen were treated with cultured, activated T cells transgenic for a T-cell receptor specifically recognizing gp100, with or without anti-CD40 mAb. In this model, the combination of anti-CD40 mAb with IL-2 led to expansion of adoptively transferred T cells and induced a more robust antitumor response. Furthermore, the expression of CD40 on bone marrow-derived cells and the presence of CD80/CD86 in the host were required for the expansion of adoptively transferred T cells. The use of neutralizing mAb to IL-12 provided direct evidence that enhanced IL-12 secretion induced by anti-CD40 mAb was crucial for the expansion of adoptively transferred T cells. Collectively, these findings provide a rationale to evaluate the potential application of anti-CD40 mAb in adoptive T-cell therapy for cancer.
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17 MeSH Terms
A genome-wide association study of inflammatory biomarker changes in response to fenofibrate treatment in the Genetics of Lipid Lowering Drug and Diet Network.
Aslibekyan S, Kabagambe EK, Irvin MR, Straka RJ, Borecki IB, Tiwari HK, Tsai MY, Hopkins PN, Shen J, Lai CQ, Ordovas JM, Arnett DK
(2012) Pharmacogenet Genomics 22: 191-7
MeSH Terms: Adult, C-Reactive Protein, Chemokine CCL2, Female, Fenofibrate, Gene Frequency, Genome-Wide Association Study, Genotyping Techniques, Humans, Hypolipidemic Agents, Inflammation, Interleukin-2 Receptor alpha Subunit, Interleukin-6, Male, Middle Aged, Polymorphism, Single Nucleotide, Tumor Necrosis Factor-alpha
Show Abstract · Added March 7, 2014
OBJECTIVE - Despite the evidence in support of the anti-inflammatory and triglyceride-lowering effects of fenofibrate, little is known about genetic determinants of the observed heterogeneity in treatment response. This study provides the first genome-wide examination of fenofibrate effects on systemic inflammation.
METHODS - Biomarkers of inflammation were measured in participants of the Genetics of Lipid Lowering Drugs and Diet Network (n=1092) before and after a 3-week daily treatment with 160 mg of fenofibrate. Two inflammatory patterns [high-sensitivity C-reactive protein-interleukin-6 and monocyte chemoattractant protein-1-tumor necrosis factor (MCP1-TNF-α)] were derived using principal component analysis. Associations between single nucleotide polymorphisms on the Affymetrix 6.0 chip and phenotypes were assessed using mixed linear models, adjusted for age, sex, study center, and ancestry as fixed effects and pedigree as a random effect.
RESULTS - Before fenofibrate treatment, the strongest evidence for association was observed for polymorphisms near or within the IL2RA gene with the high-sensitivity C-reactive protein-interleukin-6 (IL6) pattern (rs7911500, P=5×10 and rs12722605, P=5×10). Associations of the MCP1-TNF-α pattern with loci in several biologically plausible genes [CYP4F8 (rs3764563), APBB1IP (rs1775246), COL13A1 (rs2683572), and COMMD10 (rs1396485)] approached genome-wide significance (P=3×10, 5×10, 6×10, and 7×10, respectively) before fenofibrate treatment. After fenofibrate treatment, the rs12722605 locus in IL2RA was also associated with the MCP1-TNF-α pattern (P=3×10). The analyses of individual biomarker response to fenofibrate did not yield genome-wide significant results, but the rs6517147 locus near the immunologically relevant IFNAR2 gene was suggestively associated with IL6 (P=7×10).
CONCLUSION - We have identified several novel biologically relevant loci associated with systemic inflammation before and after fenofibrate treatment.
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17 MeSH Terms
Increased frequency of regulatory T cells and T lymphocyte activation in persons with previously treated extrapulmonary tuberculosis.
de Almeida AS, Fiske CT, Sterling TR, Kalams SA
(2012) Clin Vaccine Immunol 19: 45-52
MeSH Terms: Adult, Aged, Antitubercular Agents, CD4 Antigens, Case-Control Studies, Forkhead Transcription Factors, Humans, Interleukin-2 Receptor alpha Subunit, Interleukin-7 Receptor alpha Subunit, Lymphocyte Activation, Male, Middle Aged, Mycobacterium tuberculosis, T-Lymphocyte Subsets, T-Lymphocytes, Regulatory, Tuberculosis
Show Abstract · Added May 29, 2014
Extrapulmonary tuberculosis may be due to underlying immune compromise. Immunosuppressive regulatory T cells (Treg cells), and CD4(+) T lymphocytes in general, are important in the host immune response to Mycobacterium tuberculosis. We evaluated T lymphocytes from patients after recovery from extrapulmonary tuberculosis, which may reflect conditions before M. tuberculosis infection. A case-control study was conducted among HIV-uninfected adults with previously treated extrapulmonary tuberculosis and 3 sets of controls: (i) subjects with previously treated pulmonary tuberculosis, (ii) close tuberculosis contacts with M. tuberculosis infection, and (iii) close tuberculosis contacts with no infection. Monocyte-depleted peripheral blood mononuclear cells (PBMC-M) were stained for CD4(+) CD25(hi) CD127(low) FoxP3(+) cell (Treg cell) and T lymphocyte activation. Both characteristics were compared as continuous variables between groups with the Kruskal-Wallis test. There were 7 extrapulmonary tuberculosis cases, 18 pulmonary tuberculosis controls, 17 controls with M. tuberculosis infection, and 18 controls without M. tuberculosis infection. The median Treg cell proportion was highest among persons with previous extrapulmonary tuberculosis (1.23%) compared to subjects with pulmonary tuberculosis (0.56%), latent M. tuberculosis infection (0.14%), or no M. tuberculosis infection (0.20%) (P = 0.001). The median proportion of CD4(+) T lymphocytes that expressed the activation markers HLA-DR and CD38 was highest for CD4(+) T lymphocytes from persons with previous extrapulmonary tuberculosis (0.79%) compared to subjects with pulmonary tuberculosis (0.44%), latent M. tuberculosis infection (0.14%), or no M. tuberculosis infection (0.32%) (P = 0.005). Compared with controls, persons with previously treated extrapulmonary tuberculosis had the highest Treg cell frequency, but also the highest levels of CD4(+) T lymphocyte activation. Immune dysregulation may be a feature of individuals at risk for extrapulmonary tuberculosis.
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16 MeSH Terms
Podocyte injury damages other podocytes.
Matsusaka T, Sandgren E, Shintani A, Kon V, Pastan I, Fogo AB, Ichikawa I
(2011) J Am Soc Nephrol 22: 1275-85
MeSH Terms: Animals, Chimerism, Female, Interleukin-2 Receptor alpha Subunit, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nephrosclerosis, Podocytes, Transgenes
Show Abstract · Added January 25, 2012
Loss of podocytes promotes glomerulosclerosis, but whether this results from a continued primary insult or a secondary mechanism triggered by the initial loss of podocytes is unknown. We generated chimeric mice in which only a subpopulation of podocytes expressed hCD25, which is the receptor for the immunotoxin LMB2. In addition, genetic labeling of hCD25-negative cells with human placental alkaline phosphatase allowed the study of these two distinct podocyte populations. Administration of LMB2 did not cause podocyte injury in hCD25-negative control mice. In contrast, LMB2 severely damaged or sloughed off the subpopulation of hCD25-positive podocytes within the chimeric glomeruli. Moreover, hCD25-negative podocytes, which were immune to the initial toxin injury, developed injury as early as 4 d after LMB2 injection, evidenced by foot process effacement, upregulation of desmin, and downregulation of nephrin, podocin, and podocalyxin. Furthermore, the magnitude of secondary injury correlated with the magnitude of primary injury, supporting the concept of an amplified cascade of podocyte injury. In conclusion, podocyte damage can propagate injury by triggering secondary damage of "remnant" intact podocytes, even when the primary insult is short-lived. This transmission of podocyte injury may form a vicious cycle leading to accelerated podocyte deterioration and glomerulosclerosis.
Copyright © 2011 by the American Society of Nephrology
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11 MeSH Terms
Genetics and the environment converge to dysregulate N-glycosylation in multiple sclerosis.
Mkhikian H, Grigorian A, Li CF, Chen HL, Newton B, Zhou RW, Beeton C, Torossian S, Tatarian GG, Lee SU, Lau K, Walker E, Siminovitch KA, Chandy KG, Yu Z, Dennis JW, Demetriou M
(2011) Nat Commun 2: 334
MeSH Terms: Animals, Antigens, CD, CTLA-4 Antigen, Case-Control Studies, Cholecalciferol, Cohort Studies, Down-Regulation, Female, Genetic Variation, Glycosylation, Haplotypes, Humans, Male, Mice, Mice, Inbred Strains, Multiple Sclerosis, N-Acetylglucosaminyltransferases, Receptors, Interleukin-2, Receptors, Interleukin-7, Risk Factors, Signal Transduction, Sunlight
Show Abstract · Added November 15, 2013
How environmental factors combine with genetic risk at the molecular level to promote complex trait diseases such as multiple sclerosis (MS) is largely unknown. In mice, N-glycan branching by the Golgi enzymes Mgat1 and/or Mgat5 prevents T cell hyperactivity, cytotoxic T-lymphocyte antigen 4 (CTLA-4) endocytosis, spontaneous inflammatory demyelination and neurodegeneration, the latter pathologies characteristic of MS. Here we show that MS risk modulators converge to alter N-glycosylation and/or CTLA-4 surface retention conditional on metabolism and vitamin D(3), including genetic variants in interleukin-7 receptor-α (IL7RA*C), interleukin-2 receptor-α (IL2RA*T), MGAT1 (IV(A)V(T-T)) and CTLA-4 (Thr17Ala). Downregulation of Mgat1 by IL7RA*C and IL2RA*T is opposed by MGAT1 (IV(A)V(T-T)) and vitamin D(3), optimizing branching and mitigating MS risk when combined with enhanced CTLA-4 N-glycosylation by CTLA-4 Thr17. Our data suggest a molecular mechanism in MS whereby multiple environmental and genetic inputs lead to dysregulation of a final common pathway, namely N-glycosylation.
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22 MeSH Terms
Interleukin-2/interleukin-2 antibody therapy induces target organ natural killer cells that inhibit central nervous system inflammation.
Hao J, Campagnolo D, Liu R, Piao W, Shi S, Hu B, Xiang R, Zhou Q, Vollmer T, Van Kaer L, La Cava A, Shi FD
(2011) Ann Neurol 69: 721-34
MeSH Terms: Adult, Animals, Antibodies, Monoclonal, Autoimmunity, CD8-Positive T-Lymphocytes, Cell Proliferation, Central Nervous System, Cytokines, Encephalomyelitis, Autoimmune, Experimental, Female, Flow Cytometry, Granzymes, Humans, Immunotherapy, Inflammation, Interleukin-2, Killer Cells, Natural, Leukocytes, Mononuclear, Male, Mice, Mice, Inbred C57BL, Mice, Inbred Strains, Middle Aged, Multiple Sclerosis, Relapsing-Remitting, Perforin, Reverse Transcriptase Polymerase Chain Reaction, Severity of Illness Index, T-Lymphocytes, Regulatory
Show Abstract · Added March 20, 2014
OBJECTIVE - The role of natural killer (NK) cells in regulating multiple sclerosis (MS) is not well understood. Additional studies with NK cells might provide insight into the mechanism of action of MS therapies such as daclizumab, an antibody against the interleukin (IL)-2R α-chain, which induces expansion of CD56(bright) NK cells.
METHODS - In a relapsing-remitting form of the experimental autoimmune encephalomyelitis (EAE) model of MS induced in SJL mice, we expanded NK cells with IL-2 coupled with an anti-IL-2 monoclonal antibody (mAb) and evaluated the effects of these NK cells on EAE. Further, we investigated the effect of the human version of IL-2/IL-2 mAb on NK cells from MS patients and its effect on central nervous system (CNS) inflammation and pathology in a human-mouse chimera model and assessed the underlying mechanisms.
RESULTS - IL-2/IL-2 mAb dramatically expands NK cells both in the peripheral lymphoid organs and in the CNS, and attenuates CNS inflammation and neurological deficits. Disease protection is conferred by CNS-resident NK cells. Importantly, the human version of IL-2/IL-2 mAb restored the defective CD56(+) NK cells from MS patients in a human-mouse chimera model. Both the CD56(bright) and CD56(dim) subpopulations were required to attenuate disease in this model.
INTERPRETATION - These findings unveil the immunotherapeutic potential of NK cells, which can act as critical suppressor cells in target organs of autoimmunity. These results also have implications to better understand the mechanism of action of daclizumab in MS.
Copyright © 2011 American Neurological Association.
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28 MeSH Terms
Transforming growth factor beta is a major regulator of human neonatal immune responses following respiratory syncytial virus infection.
Thornburg NJ, Shepherd B, Crowe JE
(2010) J Virol 84: 12895-902
MeSH Terms: Adult, Biomarkers, Tumor, Blotting, Western, Carcinoma, Squamous Cell, Cell Differentiation, Child, Dendritic Cells, Fetal Blood, Flow Cytometry, Gene Expression Profiling, Humans, Interferon-gamma, Interleukin-2, Interleukin-4, Interleukin-6, Laryngeal Neoplasms, Oligonucleotide Array Sequence Analysis, RNA, Messenger, Respiratory Syncytial Virus Infections, Respiratory Syncytial Viruses, Reverse Transcriptase Polymerase Chain Reaction, T-Lymphocytes, Transforming Growth Factor beta, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha
Show Abstract · Added August 6, 2012
Respiratory syncytial virus (RSV) is a major cause of morbidity and mortality. Previous studies have suggested that T-cell responses may contribute to RSV immunopathology, which could be driven by dendritic cells (DCs). DCs are productively infected by RSV, and during RSV infections, there is an increase of DCs in the lungs with a decrease in the blood. Pediatric populations are particularly susceptible to severe RSV infections; however, DC responses to RSV from pediatric populations have not been examined. In this study, primary isolated DCs from cord blood and adult peripheral blood were compared after RSV infection. Transcriptional profiling and biological network analysis identified transforming growth factor beta (TGF-β) and associated signaling molecules as differentially regulated in the two age groups. TGF-β1 was decreased in RSV-infected adult-blood DCs but increased in RSV-infected cord blood DCs. Coculture of adult RSV-infected DCs with autologous T cells induced secretion of gamma interferon (IFN-γ), interleukin 12p70 (IL-12p70), IL-2, and tumor necrosis factor alpha (TNF-α). Conversely, coculture of cord RSV-infected DCs and autologous T cells induced secretion of IL-4, IL-6, IL-1β, and IL-17. Addition of purified TGF-β1 to adult DC-T-cell cocultures reduced secretion of IFN-γ, IL-12p70, IL-2, and TNF-α, while addition of a TGF-β chemical inhibitor to cord DC-T-cell cocultures increased secretion of IL-12p70. These data suggest that TGF-β acts as a major regulator of RSV DC-T-cell responses, which could contribute to immunopathology during infancy.
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25 MeSH Terms
Central nervous system (CNS)-resident natural killer cells suppress Th17 responses and CNS autoimmune pathology.
Hao J, Liu R, Piao W, Zhou Q, Vollmer TL, Campagnolo DI, Xiang R, La Cava A, Van Kaer L, Shi FD
(2010) J Exp Med 207: 1907-21
MeSH Terms: Animals, Autoimmunity, Cell Movement, Cells, Cultured, Cytotoxicity, Immunologic, Disease Models, Animal, Female, Immune Tolerance, Interleukin-17, Interleukin-2, Killer Cells, Natural, Mice, Mice, Knockout, Multiple Sclerosis, T-Lymphocytes, Helper-Inducer
Show Abstract · Added December 10, 2013
Natural killer (NK) cells of the innate immune system can profoundly impact the development of adaptive immune responses. Inflammatory and autoimmune responses in anatomical locations such as the central nervous system (CNS) differ substantially from those found in peripheral organs. We show in a mouse model of multiple sclerosis that NK cell enrichment results in disease amelioration, whereas selective blockade of NK cell homing to the CNS results in disease exacerbation. Importantly, the effects of NK cells on CNS pathology were dependent on the activity of CNS-resident, but not peripheral, NK cells. This activity of CNS-resident NK cells involved interactions with microglia and suppression of myelin-reactive Th17 cells. Our studies suggest an organ-specific activity of NK cells on the magnitude of CNS inflammation, providing potential new targets for therapeutic intervention.
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15 MeSH Terms
Impaired T-cell receptor activation in IL-1 receptor-associated kinase-4-deficient patients.
McDonald DR, Goldman F, Gomez-Duarte OD, Issekutz AC, Kumararatne DS, Doffinger R, Geha RS
(2010) J Allergy Clin Immunol 126: 332-7, 337.e1-2
MeSH Terms: Adaptive Immunity, Antigens, CD, Antigens, Differentiation, T-Lymphocyte, Case-Control Studies, Cytokines, Female, Genetic Diseases, Inborn, Humans, Immunologic Deficiency Syndromes, Interleukin-1 Receptor-Associated Kinases, Interleukin-2 Receptor alpha Subunit, Lectins, C-Type, Lymphocyte Activation, Male, Receptors, Antigen, T-Cell, T-Lymphocytes, Up-Regulation
Show Abstract · Added May 27, 2014
BACKGROUND - IL-1 receptor-associated kinase 4 (IRAK-4) is an effector of the Toll-like receptor and IL-1 receptor pathways that plays a critical role in innate immune responses. The role of IRAK-4 in adaptive immune functions in human subjects is incompletely understood.
OBJECTIVE - We sought to evaluate T-cell function in IRAK-4 deficient patients.
METHODS - We compared upregulation of CD25 and CD69 on T cells and production of IL-2, IL-6, and IFN-gamma after stimulation of PBMCs from 4 IRAK-4-deficient patients and healthy control subjects with anti-CD3 and anti-CD28.
RESULTS - Upregulation of CD25 and CD69 on T cells and production of IL-6 and IFN-gamma, but not IL-2, was significantly reduced in IRAK-4-deficient patients.
CONCLUSIONS - IRAK-4-deficient patients have defects in T-cell activation.
Copyright 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.
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17 MeSH Terms